The major objectives of this proposal are to elucidate the mechanism(s) which are responsible for tolerance development in the central nervous system (CNS), and its relationship to the hepatic metabolism of the drug. To obviate the hepatic contribution, we have developed a rat model in which tolerance to phenobarbital (PB) is produced by chronic intracerebroventricular (icv) administration of the drug. The effect of tolerance on the distribution and disposition of the drug is being explored. The role of brain neurotransmitters (e.g., acetylcholine and serotonin) is being examined by employing blocking agents as well as depletors. The influence of protein and nucleic acid inhibitors on tolerance development and maintenance will also be studied.